EP0882020B1 - Verfahren zur herstellung und isolierung von atracurium besylate - Google Patents

Verfahren zur herstellung und isolierung von atracurium besylate Download PDF

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Publication number
EP0882020B1
EP0882020B1 EP97905920A EP97905920A EP0882020B1 EP 0882020 B1 EP0882020 B1 EP 0882020B1 EP 97905920 A EP97905920 A EP 97905920A EP 97905920 A EP97905920 A EP 97905920A EP 0882020 B1 EP0882020 B1 EP 0882020B1
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EP
European Patent Office
Prior art keywords
atracurium besylate
reaction mixture
atracurium
acetate
besylate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP97905920A
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English (en)
French (fr)
Other versions
EP0882020A1 (de
Inventor
Steven A. Chamberlin
Ashok V. Bhatia
Deborah A. Davis
Keith A. Drengler
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Abbott Laboratories
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Abbott Laboratories
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine

Definitions

  • This invention relates to a process for the preparation and isolation of atracurium besylate.
  • Methyl benzenesulfonate is removed in existing methods by redissolving the crude product, obtained by precipitation with diethyl ether, in a suitable solvent such as acetonitrile and reprecipitating with diethyl ether.
  • the purification by ether precipitation is inefficient and may need to be repeated 3 to 4 times to reduce the methyl benzenesulfonate to acceptably low levels.
  • An improved purification method would require fewer operations and avoid the hazards associated with large-scale use of diethyl ether.
  • GB-A-1579822 discloses the reaction of Compound 1 with methyl benzenesulfonate in acetonitrile for 48 hours at room temperature. The filtered reaction mixture was added to dry ether to precipitate the crude product which was then filtered off, washed with dry ether and dried to yield the atracurium besylate product.
  • the present invention provides a process of producing atracurium besylate comprising the step of:
  • the present invention relates to a process of producing atracurium besylate that substantially reduces the level of impurities in the final product.
  • Compound 1, methyl benzenesulfonate and a catalytic amount of an insoluble base are combined to form a reaction mixture that is maintained for a period of time sufficient for atracurium besylate formation.
  • the reaction mixture is then filtered to remove the insoluble base, followed by subsequent atracurium besylate precipitation and collection. Collection includes the steps of filtering the reaction mixture, washing the retained material with at least one solvent selected from the group consisting of toluene and heptane, and drying the washed material, e.g. under nitrogen.
  • Another embodiment of the present invention includes forming a reaction mixture comprising, Compound 1, methyl benzenesulfonate and a catalytic amount of an insoluble base in a solvent Suitable solvents include, but is not intended to be limited to, acetonitrile.
  • the reaction mixture is maintained for a period of time sufficient for atracurium besylate formation.
  • the reaction mixture i s then filtered to remove the insoluble base and the atracurium besylate may be precipitated by diluting with an aromatic hydrocarbon with or without alcohol, and adding to a solution comprising an acetate and a lower aliphatic hydrocarbon.
  • Acetates suitable include, but are not intended to be limited to, ethyl acetate, isopropyl acetate, and methyl acetate.
  • Lower aliphatic hydrocarbons suitable include, but are not intended to be limited to, heptane, hexane, and pentane.
  • MTBE tert-butyl methyl ether
  • the use of an insoluble base in the reaction mixture has the advantage of driving the reaction to completion leading to a purer product.
  • aromatic hydrocarbons with or without an alcohol and an acetate and and a lower aliphatic hydrocarbon has the advantage of avoiding the use of diethyl ether on a large scale for the isolation of the product and reducing the number of precipitations required to purify the bulk drug.
  • Compound 1, or atracurium besylate containing incompletely converted Compound 1 may be dissolved in a solution of acetonitrile and methyl benzenesulfonate at a weight:weight:weight ratio of about 1:0.5-1.5:1.5-2.5, respectively.
  • An insoluble base including but not intended to be limited to inorganic carbonate and bicarbonates, is added to the reaction mixture preferably at a weight ratio of from about 1.0 to about 50.0 milligram (mg) per gram of atracurim, more preferably from about 1.0 to about 20.0 mg per gram of atracurim, and most preferably from about 2.5 to about 10.0 mg base per gram of atracurium.
  • Inorganic carbonates include, but are not limited to potassium carbonate, calcium carbonate, sodium carbonate, and lithium carbonate.
  • a preferred inorganic, insoluble carbonate base is sodium carbonate.
  • precipitation of atracurium besylate may be accomplished by diluting the reaction mixture with an aromatic hydrocarbon.
  • Aromatic hydrocarbons which can be used with the present invention include, but are not intended to be limited to, benzene, xylene and toluene. A most preferred aromatic hydrocarbon is toluene.
  • Yet another embodiment of the present invention utilizes precipitation by diluting with both an alcohol and an aromatic hydrocarbon.
  • Alcohols which can be used with the present invention include, but are not intended to be limited to, methanol, ethanol, 1-propanol, 1-butanol, 2-butanol, iso -butanol, and tert- butanol.
  • an alcohol is used to dilute with an aromatic hydrocarbon, the ratio of alcohol and aromatic hydrocarbon to atracurium in the reaction mixture depends upon the particular alcohol and hydrocarbon used.
  • a most preferred alcohol is isopropanol.
  • a preferred ratio is from about 0.5 to about 5 grams of isopropanol per gram of atracurium, and a more preferred ratio of from about 1.0 to about 1.5 grams of isopropanol per gram of atracurium.
  • the aromatic hydrocarbon is toluene
  • a preferred ratio is about from about 5 to about 15 grams of toluene per gram of atracurium, and a more preferred ratio is about from about 7 to about 10 grams of toluene per gram of atracurium.
  • the diluted reaction mixture may then be added slowly to a solution containing an acetate and a lower aliphatic hydrocarbon.
  • suitable acetates are ethyl acetate, isopropyl acetate, or methyl acetate.
  • Suitable lower aliphatic hydrocarbons include but are not intended to be limited to, heptane, pentane or hexane.
  • a preferred acetate is ethyl acetate and a preferred lower aliphatic hydrocarbon is heptane.
  • a preferred ratio of ethyl acetate is from about 25 to about 100 grams of ethyl acetate per gram of atracurium, and a more preferred ratio is about from about 50 to about 100 grams of ethyl acetate per gram of atracurium.
  • a preferred ratio is from about 5 to about 25 grams of heptane per gram of atracurium, and a more preferred ratio is about from about 5 to about 15 grams of heptane per gram of atracurium.
  • the solid (precipitated atracurium besylate) is then collected as described above.
  • Any residual methyl benzenesulfonate present in the final product may be removed by reprecipitating the collected product.
  • the reprecipitation may be carried out in similar fashion to the initial precipitation although the ratios of solvents may vary due to less methyl benzenesulfonate being present
  • the product may be dissolved in a reprecipitation solution, such as acetonitrile with an an aromatic hydrocarbon with or without an alcohol.
  • a preferred alcohol is isopropanol and a preferred hydrocarbon is toluene.
  • Preferred ratios of acetonitrile, isopropanol and toluene to atracurium are from about 0.5 to about 1.0 gram of acetonitrile, from about 1 to about 2 grams of isopropanol and from about 5 to about 10 grams of toluene per gram of atracurium.
  • the reprecipitation solution is then added slowly to a solution of acetate, such as ethyl acetate (from about 40 to about 50 grams per gram of atracurium) and a lower aliphatic hydrocarbon, such as heptane (from about 5 to about 10 grams per gram atracurium).
  • tert-butyl methyl ether may be substituted for the solution of acetate and a lower aliphatic hydrocarbon. If necessary, the reprecipitation can be repeated until the level of residual methyl benzenesulfonate is reduced to an acceptable level.
  • the crude product was dissolved in acetonitrile (11g ), isopropanol (27 g ), and toluene (60 g ), then diluted with an additional volume of toluene (130 ml).
  • Precipitation of the desired product by dropwise addition of this solution to to 5:1 ethyl acetate/heptanes (ethyl acetate/heptane volume of 1.2 liters) was followed by collection of the solids and washing as above.
  • the dried atracurium besylate (16.7 g, 72%) was found to have ⁇ 0.1% residual methyl benzenesulfonate, and a purity of greater than 98% by HPLC.
  • the reaction mixture contained Compound 1, methyl benzenesulfonate and acetonitrile in a weight (gram) ratio of 1:2:0.5.
  • the results are summarized below in Table 1.
  • the Peak Area Percent (PA%) is the absorbance of ultraviolet light at 265 nanometers (nm) as determined by HPLC. (IPA:Tol:EA-Hept)/Compound 1 % MeOBs (2:10:60) 0.7 (1.5:6:50) 1.7 (1.5:6:50) 2.7-3.2 (1.5:10:60) 1.0
  • Atracurium besylate containing 1.3% (HPLC peak area percent, 280 nm) Compound 1 was dissolved in acetonitrile and methyl benzenesulfonate. To this solution was added potassium carbonate and the reaction mixture was stirred for 16 hours. The reaction mixture was found to be free of Compound 1 and partially convened Compound 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Element Separation (AREA)
  • Photoreceptors In Electrophotography (AREA)
  • Paints Or Removers (AREA)
  • Organic Insulating Materials (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (24)

  1. Verfahren zur Herstellung von Atracuriumbesilat, das die folgenden Schritte umfasst:
    (a) Vereinigen von N,N'-4,10-Dioxa-3,11-dioxotridecylen-1,13-bis-tetrahydro-papaverin, Methylbenzensulfonat und einer katalytischen Menge einer unlöslichen Base zur Bildung eines Reaktionsgemischs;
    (b) Erhalten des Reaktionsgemischs für einen Zeitraum ausreichend zur Bildung von Atracuriumbesilatbildung;
    (c) Filtern des Reaktionsgemischs zum Entfernen der unlöslichen Base;
    (d) Fällen des gebildeten Atracuriumbesilates; und
    (e) Sammeln des ausgefällten Atracuriumbesilates, welches die folgenden Schritten umfasst:
    (i) Filtern des ausgefällten Atracuriumbesilates;
    (ii) Waschen des ausgefällten Atracuriumbesilates mit mindestens einem Lösungsmittel, das aus der Gruppe bestehend aus Toluol und Heptan gewählt ist; und
    (iii) Trocknen des gewaschenen, ausgefällten Atracuriumbesilates.
  2. Verfahren nach Anspruch 1, worin Schritt (a) ferner die Zugabe eines Lösungsmittels umfasst.
  3. Verfahren nach Anspruch 2, worin das Lösungsmittel Acetonitril ist.
  4. Verfahren nach Anspruch 1, worin Atracuriumbesilat durch Verdünnen des filtrierten Reaktionsgemischs mit einem aromatischen Kohlenwasserstoff gefällt wird.
  5. Verfahren nach Anspruch 4, worin das verdünnte Reaktionsgemisch zu einer Lösung hinzugegeben wird, die ein Acetat, das aus der Gruppe bestehend aus Ethylacetat, Isopropylacetat und Methylacetat gewählt ist, und einen niederen aliphatischen Kohlenwasserstoff, der aus der Gruppe bestehend aus Heptan, Hexan und Pentan gewählt ist, umfasst.
  6. Verfahren nach Anspruch 4, worin ein Alkohol hinzugefügt wird, um das Reaktionsgemisch zu verdünnen.
  7. Verfahren nach Anspruch 6, worin der Alkohol aus der folgenden Gruppe gewählt ist: Methanol, Ethanol, 1-Propanol, 1-Butanol, 2-Butanol, Isobutanol, tert-Butanol und Isopropanol.
  8. Verfahren nach Anspruch 4, worin der aromatische Kohlenwasserstoff aus der Gruppe bestehend aus Benzol, Xylol und Toluol gewählt ist.
  9. Verfahren nach Anspruch 1, das ferner den Schritt Umfällen des Atracuriumbesilates umfasst.
  10. Verfahren nach Anspruch 9, worin Umfällen des Atracuriumbesilates die folgenden Schritte umfasst:
    (a) Lösen des gewaschenen Atracuriumbesilates in einer Lösung, die Acetonitril und einen aromatischen Kohlenwasserstoff umfasst, und
    (b) Umfällen mit einem Acetat, das aus der Gruppe bestehend aus Ethylacetat, Isopropylacetat und Methylacetat gewählt ist, und einem aliphatischen Kohlenwasserstoff, der aus der Gruppe bestehend aus Heptan, Hexan und Pentan gewählt ist.
  11. Verfahren nach Anspruch 9, das ferner einen Alkohol zum Lösen des gewaschenen Atracuriumbesilates umfasst.
  12. Verfahren nach Anspruch 10, worin die Umfällung mit tert-Butylmethylether erreicht wird.
  13. Verfahren nach Anspruch 6, worin der Alkohol Isopropanol und der aromatische Kohlenwasserstoff Toluol ist.
  14. Verfahren nach Anspruch 1, worin das Gewichtsverhältnis von N,N'-4,10-Dioxa-3,11-dioxotridecylen-1,13-bis-tetrahydropapaverin, Acetonitril bzw. Methylbenzensulfonat 1,0:0,5-1,5:1,5-2,5 ist.
  15. Verfahren nach Anspruch 1, worin die unlösliche Base in dem Reaktionsgemisch im Bereich von 2,5 bis 10,0 Milligramm pro Gramm N,N'-4,10-Dioxa-3,11-dioxotridecylen-1,13-bis-tetrahydropapaverin vorliegt.
  16. Verfahren nach Anspruch 1, worin die unlösliche Base anorganische Carbonate und Bicarbonate ist.
  17. Verfahren nach Anspruch 16, worin die unlösliche Base aus der folgenden Gruppe gewählt ist: Kaliumcarbonat, Calciumcarbonat, Natriumcarbonat und Lithiumcarbonat.
  18. Verfahren nach Anspruch 1, worin das Reaktionsgemisch mit einem Alkohol in einer Menge im Bereich von 0,5 bis 5 Gramm pro Gramm N,N'-4,10-Dioxa-3,11-dioxotridecylen-1,13-bis-tetrahydropapaverin verdünnt wird.
  19. Verfahren nach Anspruch 18, worin der Alkohol Isopropanol ist.
  20. Verfahren nach Anspruch 1, worin das Reaktionsgemisch mit einem aromatischen Kohlenwasserstoff in einer Menge im Bereich von 5,0 bis 15 Gramm pro Gramm N,N'-4,10-Dioxa-3,11-dioxotridecylen-1,13-bis-tetrahydropapaverin verdünnt wird.
  21. Verfahren nach Anspruch 20, worin der aromatische Kohlenwasserstoff Toluol ist.
  22. Verfahren nach Anspruch 10, worin das Acetat Ethylacetat ist in einer Menge im Bereich von 25 bis 100 Gramm pro Gramm Atracuriumbesilat.
  23. Verfahren nach Anspruch 10, worin der aliphatische Kohlenwasserstoff Heptan ist in einer Menge im Bereich von 5,0 bis 25,0 Gramm pro Gramm Atracuriumbesilat.
  24. Verfahren nach Anspruch 10, worin Acetonitril zu dem Reaktionsgemisch in einer Menge im Bereich von 0,5 bis 1,0 Gramm Acetonitril pro Gramm Atracuriumbesilat zugesetzt wird.
EP97905920A 1996-02-16 1997-02-12 Verfahren zur herstellung und isolierung von atracurium besylate Expired - Lifetime EP0882020B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US602945 1984-04-23
US08/602,945 US5684154A (en) 1996-02-16 1996-02-16 Process for the preparation and isolation of atracurium besylate
PCT/US1997/002196 WO1997030033A1 (en) 1996-02-16 1997-02-12 Process for the preparation and isolation of atracurium besylate

Publications (2)

Publication Number Publication Date
EP0882020A1 EP0882020A1 (de) 1998-12-09
EP0882020B1 true EP0882020B1 (de) 2001-04-11

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Application Number Title Priority Date Filing Date
EP97905920A Expired - Lifetime EP0882020B1 (de) 1996-02-16 1997-02-12 Verfahren zur herstellung und isolierung von atracurium besylate

Country Status (10)

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US (1) US5684154A (de)
EP (1) EP0882020B1 (de)
JP (1) JP2000513328A (de)
AT (1) ATE200485T1 (de)
DE (1) DE69704553T2 (de)
DK (1) DK0882020T3 (de)
ES (1) ES2158499T3 (de)
GR (1) GR3036083T3 (de)
PT (1) PT882020E (de)
WO (1) WO1997030033A1 (de)

Families Citing this family (12)

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JP5213137B2 (ja) * 2006-12-06 2013-06-19 コーネル リサーチ ファウンデーション， インコーポレイテッド 中程度の持続時間の神経筋遮断剤およびそのアンタゴニスト
US8461338B2 (en) * 2007-03-08 2013-06-11 Chemagis Ltd. (1R, 1′R)-atracurium salts separation process
EP2125743A1 (de) * 2007-03-26 2009-12-02 Chemagis Ltd. Verfahren zur auftrennung von (1r,1'r)-atracuriumsalzen
EP2155684B1 (de) * 2007-05-01 2014-04-09 Chemagis Ltd. Verfahren zur herstellung von cisatracuriumverbindungen und damit assoziierte zwischenprodukte
BRPI0809892A2 (pt) * 2007-05-01 2014-09-30 Chemagis Ltd Composto de isoquinolínio, forma cristalina, composto cristalino (vii) e método para preparar cis-atracúrio
US8357805B2 (en) * 2007-06-18 2013-01-22 Chemagis Ltd. (1R,1′R)-atracurium salts separation process
BRPI0812625A2 (pt) * 2007-07-09 2019-02-19 Chemagis Ltd processo para preparar um sal de cis-atracúrio
US8354537B2 (en) * 2007-10-29 2013-01-15 Chemagis Ltd. R,R1-atracurium salts
US20110185796A1 (en) * 2008-05-01 2011-08-04 Chemagis Ltd. Cisatracurium derivatives, preparation and uses thereof
US8592451B2 (en) 2009-03-17 2013-11-26 Cornell University Reversible nondepolarizing neuromuscular blockade agents and methods for their use
CN102573794B (zh) 2009-08-19 2017-03-15 康奈尔大学 供生理注射用的半胱氨酸
CN114014806A (zh) * 2021-12-03 2022-02-08 江苏诚信药业有限公司 一种新晶型顺苯磺酸阿曲库铵及其结晶方法

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GB9015473D0 (en) * 1990-07-13 1990-08-29 Wellcome Found Neuromuscular blocking agents

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Also Published As

Publication number Publication date
WO1997030033A1 (en) 1997-08-21
GR3036083T3 (en) 2001-09-28
US5684154A (en) 1997-11-04
PT882020E (pt) 2001-09-28
DE69704553T2 (de) 2001-11-08
DE69704553D1 (de) 2001-05-17
EP0882020A1 (de) 1998-12-09
DK0882020T3 (da) 2001-08-20
ES2158499T3 (es) 2001-09-01
ATE200485T1 (de) 2001-04-15
JP2000513328A (ja) 2000-10-10

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